Unsafe at Any Exposure?

Despite resistance from the chemical industry and reticence by regulators, more and more consumer goods are now BPA-free. evidence indicates this is a good thing, says an MU scientist.
By Alan Bavley

Illustration: Man with arms outstretched, 3 clear colored bottles in front of him Title Graphic

Cheryl Rosenfeld and her University of Missouri colleagues know they're on the chemical industry's radar.

This summer it was only a matter of hours after she, neuroscience graduate student Eldin Jasarevic, developmental psychologist David Geary and other researchers published a study showing how prenatal exposure to the chemical bisphenol A seriously upsets the mating behavior of deer mice that the American Chemical Council fired back with a press release. The dose of BPA the researchers used was 250,000-times higher than what people are exposed to, the industry group said. They added that the study had "limited relevance" to human health.

Rosenfeld, an associate professor of biomedical sciences and a Bond Life Sciences Center investigator, isn't sure where the Chemical Council got that 250,000 figure. But in any case, the MU researchers repeated the study with much lower BPA doses, amounts below those experienced by pregnant women. The combined results were even more clear-cut than before: The chemical robbed male mice of their mating skills and left them unattractive to females.

Deer mice? Mating behavior? What makes a laboratory study like this such a hot button to industry?

"Our findings are relevant to humans even if industry officials do not wish to accept it," Rosenfeld explains. "The problem is, no matter the facts, the experimental controls employed, they will come back with additional, unforeseen arguments. I can't convince someone whose mind is already made up."

That's the kind of stubborn reaction MU researchers have come to expect ever since MU biology professor Frederick vom Saal first began sounding alarms in the early 1990s that even minute doses of bisphenol A can disrupt sexual development in animals, and by implication, in people as well.

Vom Saal gives Rosenfeld high praise for extending the range of BPA research "from molecular mechanisms all the way through to looking at the brain and behavior."

Multimedia: Associate Professor Cheryl Rosenfeld talks about how BPA and other endocrine disruptors could be affecting genes.  "This is very unusual to take on such a wide range and publish ground-breaking articles," vom Saal says. "This is creative research she is doing. It's also very important to public health and is likely to have an impact on how regulators deal with BPA and chemicals like BPA."

Bisphenol A is a member of a large family of chemicals called endocrine disruptors that can interfere with the natural regulation of the body's complex system of hormones. These man-made substances are contained in thousands of products and have become pervasive in the environment. They've been linked to a growing number of reproductive, growth and developmental problems in both wildlife and people.

Fish in the Great Lakes contaminated with polychlorinated biphenyls have abnormal swelling of their thyroid glands. Some scientists have suggested that endocrine disruptors found in a large pesticide spill accounted for the declining alligator population at Lake Apopka, Florida. The alligators had underdeveloped reproductive organs.

The most clear-cut effects of an endocrine disruptor on people were caused by the drug diethylstilbestrol (DES), an artificial version of the female hormone estrogen. DES was given to pregnant women in the 1950s and '60s under the mistaken idea that it would prevent miscarriages. Not only was the drug ineffective, many of the daughters of women who took DES during their pregnancy were born with reproductive system defects. By adulthood, some of these individuals developed reproductive cancers, including vaginal cancers.

BPA, developed in the 1930s, also acts like estrogen. For decades it was thought to be harmless, and it has become a common chemical in manufacturing.

Bisphenol A has been used in baby bottles and dental sealants. It lines the interior of metal food cans. It coats many cash register receipts and is present on paper currency, including American greenbacks. Almost every body of water carries detectable levels of the chemical, as do more than 90 percent of the people living in the United States.

‘We do not regulate chemicals  the way we regulate [auto safety]. 
The burden is on the scientist to prove there is a problem.’

For years, Rosenfeld, vom Saal and a growing number of other researchers have been finding worrisome evidence in laboratory animals of the harm BPA may be causing: obesity, diabetes, alterations in brain development, heightened sensitivity to drugs of abuse, reproductive abnormalities, and increased risks of breast, prostate and thyroid cancers.

Recent epidemiological studies of human populations have associated high exposures to BPA with an increased risk of heart disease, diabetes, even erectile dysfunction. To date, 11 states have banned BPA from baby drink containers. The American Chemistry Council says manufacturers haven't used the chemical in baby bottles or sippy cups for the past two years.

Other manufacturers, including drinking bottle maker Nalgene and food giant Heinz also have been removing BPA from their products. But while the FDA has called bisphenol A "a chemical of concern," it hasn't restricted its use. Providing sufficient evidence in a wide range of species to persuade federal regulators has proven difficult. Cars, for example, must undergo crash tests. There's no analogous required testing of industrial chemicals.

"We do not regulate chemicals the way we regulate [auto safety]. The burden is on the scientist to prove there is a problem," Rosenfeld says. "It is unethical to deliberately expose humans to this chemical. We can only do correlative, epidemiological studies in humans and test potential mechanisms in laboratory animals. …Yet, federal regulators and industry [spokespersons] dismiss studies in these other species as not being relevant to humans."

Rosenfeld and her colleagues at other universities have formed a consortium to coordinate their studies and share their data, and she plans to collaborate with researchers in North Carolina and Louisiana to expand her BPA research from rodents to primates.

Illustration: 2 mens' head with a superimposed curvey bottle enclosing them

This work by Rosenfeld and other researchers goes far beyond the usual concerns of traditional toxicology, says Louis Guillette, a reproductive biologist at the Medical College of South Carolina. Guillette has studied the effects of endocrine disruptors on fish, frogs, alligators and other wildlife.

"Now we're starting to look at things that are just as critical to the life history of an organism, changes in embryonic development, in behavior," Guillette says. "Each study gives us a better insight into what is going on. It's adding up."

For her part, Rosenfeld agrees that much of the havoc caused by endocrine disruptors likely occurs in the womb or early infancy, long before a child is drinking from a sippy cup: "Very few policymakers are considering the impact that exposure of pregnant women might have on their unborn offspring."

Many of our behaviors are programmed prenatally by hormones, and chemicals such as BPA can disrupt them, she adds. It could be more than a coincidence that BPA exposure levels and rates of ADHD and autism spectrum disorders among children have been rising in tandem in recent decades. "These associations are beyond a statistical fluke," she says.

The study by Rosenfeld, Jasarevic, Geary and their colleagues that set off the chemical industry's spinmeisters looked at this very issue: Can prenatal exposure to bisphenol A affect adult behavior? To answer that question, the researchers employed deer mice, a species with distinct cognitive and behavioral differences between males and females.

During breeding season, the male mice go on the prowl, seeking out as many females as they can. Enabling this behavior is their ability to navigate by visual landmarks, a skill programmed into the males by prenatal exposure to the male hormone, testosterone. It's something the females can't do. Females do, however, decide on their mates. They show their preferences by how much nose-to-nose contact they make with male suitors.

The MU researchers spiked the diet of pregnant deer mice with BPA or with a synthetic estrogen called ethinyl estradiol that is used in birth control pills. They then compared their offspring with those of mice who received an uncontaminated diet.

At first, the pups exposed to BPA or estrogen showed no physical or sensory differences compared to the control mice. But after they reached sexual maturity, tests revealed dramatic differences.

Spatial navigational skills were one affected area. To test these skills, each mouse was placed in a maze. Imagine the kind of challenges Harry Potter faced: A circular room about three feet in diameter with 12 escape holes at equal intervals along an aluminum wall. Only one of the holes leads back to the mouse's home cage; all the others are blocked. The holes all look the same, but every 90 degrees, like points on a compass, there's a visual cue attached to the wall: cut-outs of a circle, square, triangle and rectangle. Male mice whose mothers got an uncontaminated diet quickly learned to use the cues to get back to their cages. But male mice exposed in the womb to BPA or estrogen had no better navigational skills than the female mice.

The researchers also tested the mice's propensity for boldly exploring their environment, again with a challenge Harry Potter might appreciate. This time a maze in the form of a cross was suspended about three feet off the ground. Each arm of the cross was about eight inches long. The north and south arms were safely enclosed by high Lucite walls; the east and west arms were open runways – one false step and the mouse would drop to a mat below. The mice were placed in the center of the cross. Male mice that hadn't been exposed to BPA or estrogen explored the open runways, while the BPA males spent more time in sheltered areas or not moving at all.

In a third test, BPA and non-BPA male mice were placed in tiny wire cages at opposite ends of a large glass cage. A female mouse in the glass cage was free to roam from male to male to make nose contact. The females preferred the non-BPA mice by a margin of two-to-one.

Three for three, the experiments showed that BPA exposure made male mice less distinctively male. "The BPA males were almost feminized in their responses," Rosenfeld says. But can this be applied to humans?

Yes, she says. There's already analogous evidence among the sons of DES mothers. Just like male deer mice, boys generally have better spatial navigation skills than girls. Yet a previous study demonstrated that these skills are dampened in boys whose mothers took DES during pregnancy.

Rosenfeld and her colleagues are now looking at whether BPA's influences extend beyond prenatal-behavioral programming to how BPA might affect parental responses. To address this concern, the researchers are turning to the California mouse, a species unique for its monogamy. These mice not only stay faithful to each other, males take on an important parenting role — both mom and dad groom their pups by licking them.

In her laboratory, Rosenfeld keeps each family unit of California mice in a separate cage; some are fed BPA-laced mouse chow tinted pink, while the rest get regular chow. Each mouse family spends time observed by a camera linked to a sophisticated computer tracking system. This close monitoring will make it possible for Rosenfeld to look for parenting differences between the two groups.

"Does BPA affect paternal response? Even subtle changes, such as a little neglect or less grooming of pups might equate to later profound differences as the offspring reach adulthoood," Rosenfeld says. "I think for humans that can have huge implications."

Rosenfeld has been asking questions like these ever since she squinted through an eyepiece to take a close look at pond scum in her high school biology class in Skokie, Ill. She eventually went to the University of Illinois at Urbana-Champaign to study biology, then veterinary medicine. She decided to become a vet, she says, because her parents never allowed animals in their house. She had to play with the neighbor's dog to satisfy her interest in animals.

While at Illinois, Rosenfeld happened to volunteer for work in a lab. There she discovered her true passion was research. "I liked vet school. I like animals, but I like understanding how things are put together," she says. "Even the small discoveries along the way, they're exciting to me."

And as she helped fellow veterinary students study during review sessions, Rosenfeld also found she enjoyed teaching. "If I wanted to teach and do research, I needed a PhD," she says. So after receiving her DVM, Rosenfeld came to MU in 1995 to pursue a doctorate in animal science and reproductive biology. In 2004, Rosenfeld joined the faculty. Last year she was granted tenure.

At MU, Rosenfeld has been able to integrate her interests in animal behavior, endocrinology and reproduction: "This is exactly where I want to be right now. I feel privileged to be paid to do what I do."

Rosenfeld's work on endocrine disruptors has crucial implications beyond academia. Her findings suggest an immediate need to reduce everyone's exposure to the chemicals. Rosenfeld feels compelled to let the public know what's at stake. She's appeared on radio shows and been interviewed in popular magazines about her research.

"We need to put things in words that people can understand, not in scientific jargon," she says. "This is one of our most important roles as scientists. We know our research. It is our job to communicate our findings, particularly if there may be cause for concern." *

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